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WO2014141082A1 - Agent pour la prophylaxie et le traitement de maladies cancéreuses - Google Patents

Agent pour la prophylaxie et le traitement de maladies cancéreuses Download PDF

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Publication number
WO2014141082A1
WO2014141082A1 PCT/IB2014/059659 IB2014059659W WO2014141082A1 WO 2014141082 A1 WO2014141082 A1 WO 2014141082A1 IB 2014059659 W IB2014059659 W IB 2014059659W WO 2014141082 A1 WO2014141082 A1 WO 2014141082A1
Authority
WO
WIPO (PCT)
Prior art keywords
drugs
treatment
dose
tumor
animals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2014/059659
Other languages
English (en)
Russian (ru)
Inventor
Рахимджан Axметджанович РОЗИЕВ
Анна Яковлевна ГОНЧАРОВА
Кенес Тагаевич ЕРИМБЕТОВ
Владимир Константинович ПОДГОРОДНИЧЕНКО
Виктор Владимирович ХОМИЧЕНОК
Наталья Евгеньевна НОВОЖИЛОВА
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TIACEN Ltd
Original Assignee
TIACEN Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from RU2013111415/04A external-priority patent/RU2522449C1/ru
Priority claimed from RU2013111416/15A external-priority patent/RU2521390C1/ru
Application filed by TIACEN Ltd filed Critical TIACEN Ltd
Priority to EA201591772A priority Critical patent/EA026332B1/ru
Priority to US14/775,698 priority patent/US9949961B2/en
Priority to EP14764332.4A priority patent/EP2974726A4/fr
Publication of WO2014141082A1 publication Critical patent/WO2014141082A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to a new tool, which is a derivative of rhodanine, which has a prophylactic, antiproliferative and antimetastatic effect.
  • the specified tool can find application in medicine and pharmacology for the prevention and / or treatment of tumor diseases of different localization.
  • ITCs isothiocyanates
  • ITC contained in plant products to prevent the development of cancer is only partially realized when they are consumed by people. This may be due to their irregular, inadequate or excessive consumption.
  • ITC are weak mutagens and their ability to induce the formation of malignant tumors in animals is shown in separate model experiments.
  • Cruciferous vegetables are known to contain a large number of glucosinolates, of which enzymatically violation of the integrity of plants forms a number of isothiocyanates. It has been established that natural isothiocyanates to varying degrees in in vitro systems inhibit cell proliferation by suppressing the cell origin of the cell type and, in addition, induce apoptosis of tumor cells.
  • ITCs are contained in the form of thioglycoside conjugates called glucosinolates, which have a faint odor and do not have an irritating effect on the mucous membrane and are gradually hydrolyzed by enzymes with the release of ITC.
  • glucosinolates thioglycoside conjugates
  • FEITC phenylethylzothiocyanates
  • chemoprotective chemoprotective agents for example glucosinolates, which are metabolic precursors of isothiocyanates, are described, for example, in US Pat. No. 5,968,505 or US Pat. No. 5,968,567. Such agents reduce carcinogens in animals.
  • RU2405782C2 describes 5-quinazolin-6-ylmethylene-2-thioxothiazolidin-4-one as an intermediate for the preparation of 5 - [1-quinazolin-6-ylmeth- () -ylidene] -2-substituted amino] thiazol-4- it is intended for the treatment of cancer, especially solid tumors, most preferably lung cancer, breast cancer, colon cancer and prostate cancer.
  • the objective of the present invention is to find new tools for the prevention and / or treatment of tumor diseases of various localization, which simultaneously have the following characteristics:
  • the invention relates to a new tool with a prophylactic, antiproliferative and antimetastatic effect for the prevention and treatment of tumor diseases, which is a derivative of rhodanine of the following structural formula (I):
  • the compounds of the present invention do not have an unpleasant odor
  • the resulting compounds are a powder having a slight cruciferous odor that can be easily tabletted.
  • the resulting compounds were stable during storage, and were tested for prophylactic and antitumor efficacy.
  • the proposed derivatives of rhodanine have additional qualities due to the content of a thioglycolic acid residue in them, which bind highly toxic water-soluble salts of heavy metals and, according to the invention, can also be used to remove heavy metal ions, as well as to prevent exposure to adverse factors for people living in environmentally polluted areas to prevent and neutralize the effects of harmful substances in industrial conditions, especially the metallurgical industry.
  • the use of compounds of the present invention exhibiting antiproliferative and antimetastatic effect, for the treatment of tumor diseases was not previously known.
  • Example 1 To solve this problem were formed 3 groups of male rats of the Wistar line with a mass of 150-200 g of 16 animals each. Rats of the control group were injected intraperitoneally with DENA at a dose of 30 mg / kg / week. The dose was administered in 2 divided doses: Monday and Thursday. The animals of the experimental groups of DEN were administered in a similar manner. Additionally, rats of the experimental groups, drug 1 and 2 were added to drinking water on the basis that they receive 25 mg / kg of body weight / day with water. Animals started taking the drug 3 weeks before the start of N-diethylnitrosamine administration to create a protective background in the animal’s body and then for 2.5 months.
  • the mass of rats was controlled. After opening the animals, the liver was weighed, the tumors on its surface were visually counted, and photographs were taken.
  • the drugs have a preventive effect against tumors in the liver of rats during chemical carcinogenesis.
  • Example 2 Test system. To study the antitumor (antiproliferative) and antimetastatic properties of preparations 1 and 2, 120 male mice of the first generation of CBAxC57B1 / 6 hybrids were used: 10-12 each group. ⁇ 10 6 cells (-0.2 cm 3 ) were implanted in the hind paw of animals. Doses and dosage regimens of drugs 1 and 2. The method of drug administration was per os, which meant adding drugs 1 and 2 to drinking water given to animals. The introduction of drugs 1 and 2 into drinking water was carried out in two schemes: for 3 weeks only after implantation and for 4 weeks with the beginning of the introduction of the previous implantation. The experimental groups, doses and timing of administration are shown in table 2.
  • Antitumor (antiproliferative) and antimetastatic activity of drugs 1 and 2 were evaluated by the change in tumor volume and the number of metastases in the lungs.
  • the number of metastases was estimated on the 21st day after tumor implantation (28th day after the start of the administration of drugs 1 and 2 according to the 1st scheme). To do this, lungs were removed from decapitated animals under anesthesia and the latter were transferred to Buen's fluid.
  • Counting metastases was performed visually.
  • the volume of the neoplasm was estimated using the ellipsoid formula (1). Duration of measurement: 7, 14 and 21 days after implantation.
  • di, d 2 , d 3 are mutually perpendicular sizes of the tumor.
  • Tumor volume is indicated in mm, its size in mm, body weight in grams, after the ⁇ sign an average error is given.
  • the tumor volume is indicated mm 3 , its size in mm,
  • drugs 1 and 2 have the ability to inhibit the growth of Lewis carcinoma in mice. Inhibition is dose dependent. With the introduction of drugs 1 and 2 at a dose of 25 mg / kg of animal weight, the inhibition of tumor growth is more pronounced than with the dose of 5 mg / kg. But with the introduction of both doses, the size of the tumors is statistically significantly different from the size of the control group of animals. Preliminary administration of drugs 1 and 2 within 1 week before tumor inoculation enhances the effectiveness of the drugs. A study of the effects of drugs 1 and 2 on metastasis revealed that drugs at a dose of 25 mg / kg animal weights significantly reduced the number of lung metastases when administered after tumor implantation. A downward trend in the number of metastases in the lungs was also observed with the administration of drugs 1 and 2 at a dose of 5 mg / kg of body weight.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un nouveau produit présentant des dérivés de rhodanine qui possède une action prophylactique, anti-proliférative et anti-métastasique. Le présent produit peut s'utiliser en médecine, en pharmacologie pour le traitement et/ou la prévention de maladies cancérieuses de localisation différente.
PCT/IB2014/059659 2013-03-14 2014-03-12 Agent pour la prophylaxie et le traitement de maladies cancéreuses Ceased WO2014141082A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EA201591772A EA026332B1 (ru) 2013-03-14 2014-03-12 Применение производных роданина для профилактики и/или лечения опухолевых заболеваний
US14/775,698 US9949961B2 (en) 2013-03-14 2014-03-12 Agent for the prophylaxis and/or treatment of neoplastic diseases
EP14764332.4A EP2974726A4 (fr) 2013-03-14 2014-03-12 Agent pour la prophylaxie et le traitement de maladies cancéreuses

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
RU2013111415/04A RU2522449C1 (ru) 2013-03-14 2013-03-14 Средство, обладающее антипролиферативным и антиметастатическим действием, для лечения опухолевых заболеваний
RU2013111415 2013-03-14
RU2013111416/15A RU2521390C1 (ru) 2013-03-14 2013-03-14 Производное роданина и средство для профилактики опухолевых заболеваний
RU2013111416 2013-03-14

Publications (1)

Publication Number Publication Date
WO2014141082A1 true WO2014141082A1 (fr) 2014-09-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/059659 Ceased WO2014141082A1 (fr) 2013-03-14 2014-03-12 Agent pour la prophylaxie et le traitement de maladies cancéreuses

Country Status (4)

Country Link
US (1) US9949961B2 (fr)
EP (1) EP2974726A4 (fr)
EA (1) EA026332B1 (fr)
WO (1) WO2014141082A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116196415B (zh) * 2022-12-07 2023-08-01 浙江省肿瘤医院 用于增敏pd-1抗体的混合制剂及其使用方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU119529A1 (ru) * 1958-06-23 1958-11-30 С.Н. Баранов Способ получени роданина
US5968505A (en) 1995-09-15 1999-10-19 Johns Hopkins School Of Medicine Cancer chemoprotective food products
US20030195238A1 (en) 2000-05-11 2003-10-16 Gil Ana Martinez Enzyme inhibitors
RU2391342C2 (ru) * 2004-10-14 2010-06-10 Ф.Хоффманн-Ля Рош Аг Новые азаиндолтиазолиноны в качестве противораковых агентов
RU2405782C2 (ru) 2004-10-14 2010-12-10 Ф.Хоффманн-Ля Рош Аг Хиназолинилметилентиазолиноны в качестве cdk-1 ингибиторов
RU2010129238A (ru) * 2008-01-18 2012-01-20 Индена С.П.А. (It) Применение производных изотиоцианата в качестве противомиеломных средств

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU119529A1 (ru) * 1958-06-23 1958-11-30 С.Н. Баранов Способ получени роданина
US5968505A (en) 1995-09-15 1999-10-19 Johns Hopkins School Of Medicine Cancer chemoprotective food products
US5968567A (en) 1995-09-15 1999-10-19 John Hopkins School Of Medicine Method of preparing a food product from cruciferous sprouts
US20030195238A1 (en) 2000-05-11 2003-10-16 Gil Ana Martinez Enzyme inhibitors
RU2391342C2 (ru) * 2004-10-14 2010-06-10 Ф.Хоффманн-Ля Рош Аг Новые азаиндолтиазолиноны в качестве противораковых агентов
RU2405782C2 (ru) 2004-10-14 2010-12-10 Ф.Хоффманн-Ля Рош Аг Хиназолинилметилентиазолиноны в качестве cdk-1 ингибиторов
RU2010129238A (ru) * 2008-01-18 2012-01-20 Индена С.П.А. (It) Применение производных изотиоцианата в качестве противомиеломных средств

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BUCK, JOHANNES S. ET AL.: "Rhodanines. I. Derivatives of beta-phenylethylamines.", J. AM.CHEM. SOC, vol. 53, no. 7, 1931, pages 2688 - 2692, XP055281719 *
C. ERNST REDEMANN; ROLAND N. ICKE; GORDON A. ALLES: "Rhodanine", ORG. SYNTH.; COLL., vol. 3, 1955, pages 763
LEONARD: "Rhodanines 1. derivates of (3-phenylethylamines", J. AM. CHEM. SOC., vol. 53, no. 7, 1931, pages 2688 - 2692
See also references of EP2974726A4 *

Also Published As

Publication number Publication date
EP2974726A4 (fr) 2017-01-04
EA201591772A1 (ru) 2015-12-30
EP2974726A1 (fr) 2016-01-20
US9949961B2 (en) 2018-04-24
US20160038472A1 (en) 2016-02-11
EA026332B1 (ru) 2017-03-31

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